The extensive variation at some of the immune response genes is central amongst the host genetic determinants that contribute to the variability in risk of virtually all human diseases. We have studied the genetic effects of the highly polymorphic KIR and HLA loci, as well as other related, less polymorphic loci on several diseases. Our contributions to the general understanding of these effects are summarized here. As part of the innate immune system, NK cells present the first line of defense against viral infections and tumors. NK cell effector functions, such as cytotoxicity and cytokine release, are controlled by integrated signals from a large panel of both activating and inhibitory receptors. Killer cell immunoglobulin-like receptors (KIRs) on NK cells and their ligands, HLA class I molecules, play an essential part in this tight regulation. Both the KIR gene cluster and the HLA class I loci are extraordinarily diverse, which has led to the hypothesis that NK cell immune responses are genetically predetermined to some extent. This is supported by previous epidemiological observations by my laboratory that KIR/HLA compound genotypes with a supposedly activating profile (i.e., presence of activating KIR or lack of inhibitory KIRs or their respective ligands) are associated with resistance to HCV and HIV infection, slower HIV disease progression, and better reproductive fitness. A significant association has been described between slower HIV-1 disease progression and the expression of an activating NK cell receptor, KIR3DS1, in conjunction with its putative ligand, HLA-B Bw4 alleles with an isoleucine at position 80 (referred to as HLA-B Bw4-80I). These epidemiological data were the first to implicate specific NK cell receptor genes in modulating HIV-1 pathogenesis, but the functional basis of the epidemiological association between these KIR/HLA compound genotypes and control of HIV-1 replication and disease progression have not yet been identified. In conjunction with collaborators at Harvard medical school, we demonstrated that NK cells are able to suppress HIV-1 replication in vitro in a dose- and cell contactdependent manner. Furthermore, we showed that NK cells expressing KIR3DS1 strongly and significantly inhibited HIV-1 replication in target cells expressing HLA-B Bw4-80I relative to NK cells that do not express KIR3DS1. These data provide the first functional evidence that variation at the KIR locus influences the effectiveness of NK cell activity in the containment of HIV-1 replication and specifically provide an initial functional correlate for the protective effect of the KIR3DS1/HLA-B Bw4-80I compound genotype from HIV-1 disease progression described in previous epidemiological studies. These data suggest a more important role of effector cells of the innate immune system in the control of HIV-1 replication than traditionally thought, which will help to guide the development of antiviral strategies directly targeting innate immunity. It has been proposed that improved resistance to virus infections among KIR2DL3/HLA-C1positive individuals may be the result of weaker NK cell inhibition through KIR2DL3 compared with NK cell inhibition through KIR2DL1 in KIR2DL1/HLA-C2positive individuals. In order to characterize NK cell responsiveness in the context of different HLA-C alleles, we collaborated with Dr. Barbara Rehermann at the NIDDK to study the kinetics of NK cell responses in a unique and well-characterized cohort of subjects with distinct KIR/HLA compound genotypes using an in vitro model of infection with influenza A virus (IAV). Multicolor flow cytometry revealed that the HLA-Cinhibited NK cell subset in HLA-C1 homozygous subjects was larger and responded more rapidly in IFN-&#947; secretion and CD107a degranulation assays than its counterpart in HLA-C2 homozygous subjects. These results provide functional evidence for differential NK cell responsiveness depending on KIR/HLA genotype and may provide useful insights into differential innate immune responsiveness to viral infections. Overall, these functional studies have been exceptionally rewarding in that they explain and confirm the genetic data, and thereby provide solid information to use in development of potential therapies. Nonhuman primates such as macaques and sooty mangabeys are an essential component in the development of an effective AIDS vaccine. In collaboration with Dr. David Watkins at the University of Wisconsin, we have shown the importance of the MHC class I and II loci in the control of SIV infection in macaques. Specifically, Mamu-B*08, Mamu-DRB1*1003 and -DRB1*0306 were enriched in a cohort of SIV-infected Rhesus Macaque Elite Controllers. The data derived from these studies may provide a good model to understand the correlates of MHC associated immune protection and viral containment in human elite controllers and further our understanding of HIV vaccine design. In collaboration with investigators at the University of Washington we analyzed mother-child HLA concordance and maternal HLA homozygosity in a Kenyan perinatal cohort receiving antenatal zidovudine. HLA concordance was scored as the number of shared class I alleles, and relative risk estimates were adjusted for maternal HIV-1 load. The results showed that mother-child HLA concordance and maternal HLA homozygosity increased the risk of HIV-1 infection in infants for overall, in utero, and breast-feeding transmission. These data are consistent with previous evidence indicating that HLA-mediated immune responses are important drivers of HIV-1 selection and HLA diversity. The results also suggest a role for alloimmune responses in vertical transmission of HIV-1, which is intriguing because similar studies have indicated that concordance and alloimmune responses may also alter the risk of heterosexual HIV-1 transmission. Thus, further studies of the role played by HLA class I and II and cellular alloimmune responses in both vertical and heterosexual HIV-1 transmission are warranted. The natural killer cells at the site of placentation express KIR that can bind to HLA-C molecules on trophoblast cells. Both these gene systems are polymorphic and we previously showed an association of particular maternal KIR/fetal HLA-C genotypes in pre-eclampsia. Pre-eclampsia and recurrent miscarriage (RM) share the pathogenesis of defective placentation. In collaboration with Dr. Ashley Moffett at the University of Cambridge, couples with RM were genotyped. The results indicated that KIR2DS1 is protective because the lack of this gene in RM women was highly significant. This finding makes biological sense because KIR2DS1 is the activating receptor for HLA-C group 2 allotypes and so the functional effect would be to overcome the strong inhibition mediated by a C2-KIR2DL1 interaction. The findings help to refute the pervasive idea that the function of trophoblast HLA class I molecules on the invading trophoblast is to inhibit killing by NK cells. Many researchers have found that uterine NK (uNK) cells do not kill trophoblast but instead produce a variety of cytokines and chemokines that modulate invasion and homing to the spiral arteries. Importantly, levels of angiogenic factors and chemokines produced by uNK cells are reduced following KIR2DL1 binding [summary truncated at 7800 characters]